The present invention relates to methods for increasing cellular levels of glutathione and treatments utilizing same.
It is known that the intracellular levels of glutathione can be important with respect to cell function. For example, reduced glutathione levels are found in many disease states, e.g., immune compromised patients.
Further, it is known that glutathione provides many benefits in protecting cells against damage. For example, glutathione protects cells against the effects of free radicals and of oxygen intermediates. Free radicals are molecules with an unpaired electron creating an unstable and highly reactive molecule. Oxygen free radicals are highly reactive with biological macromolecules such as found in cell membranes and thereby can induce cell damage.
Indeed, a number of methods of treatments have been devised using the stimulation of intracellular glutathione levels to treat a number of disease states. Such disease states include: reperfusion injury (see U.S Pat. No. 5,095,027); hepatic disease; adult respiratory distress syndrome; immune disorders; and latent viral infections.
Unfortunately, according to the majority of literature in the art, intracellular glutathione levels cannot be increased by merely attempting to load the cell with glutathione. See, U.S. Pat. No. 4,784,685 "there are several reports on particular biological systems indicating that glutathione itself is not transported into cells" (column 2, lines 37-39).
Some methods are known to increase cellular levels of glutathione. Glutathione is composed of three amino acids: glutamic acid; cysteine; and glycine. Although administration to animals of the amino acid precursors of glutathione may produce an increase in cellular glutathione, there is a limit to the effectiveness of this procedure.
Concentrations of glutathione are dependent on the supply of cysteine. Cysteine can be derived from dietary protein and by trans-sulfuration from methionine in the liver. Cysteine administration is not an ideal method for increasing intracellular glutathione concentrations. Cysteine is rapidly metabolized and is very toxic (see U.S. Pat. No. 4,434,158 "cysteine cannot be administered intravenously due to its toxic effects on the system" (column 2, lines 6-8)).
A couple of compounds are known for increasing glutathione levels in the cells. For example, it is known to administer N-acetyl-L-cysteine, L-2-oxothiazolidine-4-carboxylate, and glutathione esters. Examples of patents relating to L-2-oxothiazolidine-4-carboxylate and glutathione esters are as follows: 4,335,210; 4,434,158; 4,438,124; 4,647,751; 4,665,082; 4,710,489; and 4,784,685.
L-2-oxothiazolidine-4-carboxylate is transported into most cells where it is converted by the action of 5-oxo-L-prolinase in the presence of adenosine triphosphate to produce S-carboxyl cysteine. S-carboxyl cysteine is then decarboxylated to produce cysteine. Cysteine is then rapidly used for glutathione synthesis.
There may be at least certain advantages achieved by L-2-oxothiazolidine-4-carboxylate over N-acetyl-L-cysteine and/or glutathione esters. These potential advantages the inventor believes include, inter alia, the fact that L-2-oxothiazolidine-4-carboxylate is more rapid and has better bioavailability as a precursor of cysteine; in certain circumstances, it is preferable to supply adequate cysteine to restore or maintain cellular functions including glutathione synthesis.
However, there are some cells and body tissues wherein it is difficult to transport L-2-oxothiazolidine-4-carboxylate into the cells. Such cells may include at least select brain cells, spinal cord cells, peripheral cells in the nervous system, skin, and the cornea. Some such cells may lack a mechanism for transporting L-2-oxothiazolidine-4-carboxylate into the cells. Even in cells having the ability to transport L-2-oxothiazolidine-4-carboxylate into the cells, the transport may be rate limiting as to the production of glutathione. Therefore, it may be desirable to bypass the transport. Still further, in some structures, such as the cornea or skin, cornified protective surfaces may prevent the transport of L-2-oxothiazolidine-4-carboxylate into the cells.
Although L-2-oxothiazolidine-4-carboxylate provides a mechanism for increasing intracellular glutathione levels in most cells, there are some cells and tissues wherein this mechanism cannot be used or one may want to avoid the mechanism.